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Bevacizumab/Lomustine Combinations Falls Short in Phase III Glioblastoma Trial

Shannon Connelly
Published Online:10:12 PM, Tue January 30, 2018

Wolfgang Wick, MD
Treatment with lomustine (Gleostine) plus bevacizumab (Avastin) provided a slightly improved progression-free survival (PFS), but did not demonstrate an overall survival (OS) advantage over treatment with lomustine alone in patients with progressive glioblastoma, according to results of a randomized phase III trial published in the New England Journal of Medicine.

There were a total of 329 OS events (75.3%) in patients who received the combination, which did not meet the endpoint for a statistically significant benefit. The median OS was 9.1 months (95% CI, 8.1-10.1) in the group of patients who received the combination of lomustine and bevacizumab and 8.6 months (95% CI, 7.6-10.4) in the monotherapy group (HR, 0.95; 95% CI, 0.74-1.21). Locally assessed PFS was 4.2 months in the combination group versus 1.5 months in the monotherapy group (HR, 0.49; 95% CI, 0.39-0.61).

“Adding bevacizumab to lomustine did not confer a survival advantage over lomustine alone but prolonged progression-free survival somewhat. This benefit was consistent across the assessments of the trial, although there were some local and central deviations,” Wolfgang Wick, MD, et al concluded in their report.

A total of 437 patients with progression of disease after chemoradiotherapy were initially randomized in a 2:1 ratio to receive lomustine plus bevacizumab (n = 288) or lomustine alone (n = 149). The study was conducted between November 2011 and December 2014 at 38 institutions in 8 countries. The intention-to-treat analysis included 98.7% of patients from the lomustine single-agent arm (n = 149) and 98.3% of patients in the combination arm (n = 288) who received treatment.

To be eligible for enrollment, patients had to have histologic confirmation of glioblastoma with unequivocal first progression after chemoradiotherapy at least 3 months following the end of radiotherapy. Patients who had undergone antiangiogenic treatment were excluded. Radiotherapy at a dose of ≤65 Gy with stereotactic radiosurgery or brachytherapy was allowed if recurrence was histologically proven. Only non–enzyme-inducing antiepileptic drugs were allowed.

Patient characteristics were well balanced between the 2 groups. A total of 265 patients (60.6%) were male and 172 patients (39.4%) were female. The median age was 57.7 (range, 21.2-82.3 years). The majority of patients (55.1%) had an World Health Organization (WHO) performance status of 1. Forty-seven patients (10.8%) had an WHO performance status of 2, and 149 patients (34.1%) had an WHO performance status of 0.

Investigators assessed the methylation status of the promoter of O6-methylguanine–DNA methyltransferase (MGMT). Health-related quality of life and neurocognitive function were evaluated at baseline and every 12 weeks. The primary endpoint of the trial was OS.

A total of 104 patients on the study (23.8%) had methylated MGMT, 125 (28.6%) had unmethylated MGMT, 36 (8.2%) had an undetermined status, and data was not available for 172 patients (39.4%).

Patients in the monotherapy group received lomustine at a dose of 110 mg/m2 every 6 weeks (maximum dose, 200 mg). Patients in the combination group received 90 mg/m2 lomustine every 6 weeks (maximum dose, 160 mg) plus bevacizumab at a dose of 10 mg/kg every 2 weeks. In the combination group, the dose of lomustine was increased to 110 mg/m2 (maximum dose, 200 mg) for the second cycle if there were no hematologic adverse events (AEs). The median number of 6-week treatment cycles was 3 in the combination group and 1 in the monotherapy group.

Grade 3 to 5 AEs occurred in 38.1% of the patients in the monotherapy group and 63.6% of the patients in the combination group. Serious AEs (grade 3-5) of special interest were pulmonary embolism, arterial hypertension, and hematologic AEs. One patient in the monotherapy group died from a lung infection that was unrelated to the tumor. Five deaths were reported in the combination group, 2 from myocardial infarction and 1 each from large-intestine perforation, sepsis, and intracranial hemorrhage.

“There were no unexpected findings from assessments of toxic effects, although absolute numbers were higher and deaths more frequent in the combination group than in the monotherapy group. Although important given the lack of overall survival benefit, the higher numbers of adverse effects should be assessed relative to the longer treatment period in the combination group,” investigators wrote in their report.

The main reason for discontinuing treatment was disease progression, in 120 of 144 patients (83.3%) in the lomustine group, 186 of 264 patients (70.5%) for lomustine in the combination group, and 208 of 264 patients (78.8%) for bevacizumab in the combination group. The discrepancy between stopping bevacizumab and lomustine in the combination group was a result of treatment scheduling or toxic effects (15 of 144 patients [10.4%] in the monotherapy group, 53 of 264 [20.1%] for lomustine in the combination group, and 38 of 264 [14.4%] for bevacizumab in the combination group).

No significant differences were noted between the treatment arms in terms of health-related quality of life until week 36. At week 36, changes tended to favor the monotherapy arm in terms of both global health status and social functioning. Adherence tended to favor the combination group though (71.2% vs 50.0% with lomustine monotherapy).

Patients who experienced disease progression on the trial—65.9% of the patients in the monotherapy group and 53.0% of the patients in the combination group—received further therapy. Of 401 patients with documented progression, 368 had evaluable follow-up data. The majority of patients received subsequent chemotherapy (32.6% in the monotherapy group and 38.3% in the combination group), bevacizumab (35.5% in the monotherapy group and 18.7% in the combination group), or targeted therapies (42.0% in the monotherapy group and 23.5% in the combination group).
Wick W, Gorlia T, Bendszus M, et al. Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med. 2017;377:1954-1963. doi: 10.1056/NEJMoa1707358.

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